tbuckley/cabot-search huggingface dataset:
Physician Adenoma Detection Rates and Colorectal Cancer
Authors: Edwin Colloff
Journal: JAMA (2022)

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Physician Adenoma Detection Rates and Colorectal Cancer
Authors: Michael J. Schell, Clement K. Gwede, Mark Friedman
Journal: JAMA (2022)

To the Editor A recent study1 of adenoma detection rate, which is the most important quality measure in colonoscopy,2 found that a higher adenoma detection rate was associated with lower postcolonoscopy colorectal cancer. We have several concerns about this study.
Gender-specific psychosocial stressors influencing mental health among women elite and semielite athletes: a narrative review
Authors: Michaela Pascoe, Aurélie Pankowiak, Mary Woessner, Camilla L Brockett, Clare Hanlon, Ramón Spaaij, Sam Robertson, Fiona McLachlan, Alexandra Parker
Journal: British Journal of Sports Medicine (2022)

Elite and semielite athletes commonly experience mental health concerns and disorders. Compared with men athletes, women athletes are at greater risk of a range of psychological stressors that contribute to health concerns and mental health disorders, which can impact their career satisfaction and longevity. In order to address and improve the mental health of women athletes, it is necessary to simultaneously tackle the gender specific psychosocial stressors that contribute to mental health outcomes. This narrative review examines the gender-specific stressors that affect mental health and well-being in women athletes, some of which are modifiable. Psychosocial stressors identified include exposure to violence, be it psychological, physical or sexual in nature, which can result in a myriad of acute and long-lasting symptoms; and inequities as reflected in pay disparities, under-representation in the media, fewer opportunities in leadership positions and implications associated with family planning and motherhood. Strategies to promote mental health in women athletes should be considered, and where possible, should proactively address gender-specific stressors likely to influence mental health in order to maximise positive outcomes in women athletes.
The challenge for COP27
Authors: Alison Shepherd
Journal: BMJ (2022)

A farmer stands among the carcasses of his livestock as drought threatens 2.8 million people in Kenya with starvation.Governments, organisations, and activists are preparing for COP27 in Egypt next month, in a year in which the world has been hit by a range of climate related disasters, from hurricanes and heatwaves to long term droughts and massive flooding.The UN states categorically that "climate change is the single biggest health threat facing humanity" that is already taking the lives of 13 million people a year.Will this year's global summit be able to make a difference?
Improved control of SARS-CoV-2 by treatment with a nucleocapsid-specific monoclonal antibody
Authors: Tanushree Dangi, Sarah Sanchez, Jacob Class, Michelle Richner, Lavanya Visvabharathy, Young Rock Chung, Kirsten Bentley, Richard J. Stanton, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster
Journal: Journal of Clinical Investigation (2022)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine and then transferred sera from these mice into naive mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific mAb exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) against infected cells. To our knowledge, these findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based mAb therapies to treat COVID-19.
Towards net zero healthcare
Authors: Rachel Stancliffe, Aarti Bansal, Georgina Sowman, Frances Mortimer
Journal: BMJ (2022)

What you need to know• Reduce use of health services and improve healthcare efficiency by integrating the following principles into daily clinical practice and quality improvement: prevention, patient empowerment, lean systems, and low carbon alternatives • Encourage sustainable healthcare principles in all populations (including those currently under-served) to reduce health inequalities • Consider strategies to reduce duplication and waste, for example, when booking appointments, requesting investigations, prescribing, allocating resources, and arranging patient or staff travel Case-A 47 year old woman who takes metformin and amlodipine for type 2 diabetes and hypertension visits her GP to discuss her HbA1C levels, which have been steadily increasing.She is a single mother with two children at school and works full time in an office.They discuss the option of increasing her diabetes medication and how.High quality control of long term conditions with medication has a lower burden on patients' physical, mental, and social health-as well as a lower carbon footprint-than poor control, which may result in complications and admissions.However, the patient doesn't want to increase her medication as she experiences several side effects from the medicines she already takes.Our essential life support systems-water, air, food, and a stable climate-are being destroyed by the global climate and ecological emergency.This is claiming millions of lives and its impacts are disproportionately felt by people who are poorer and more vulnerable. 1A report from Health Care Without Harm suggests that the climate footprint of healthcare worldwide is equivalent to 4.4% of global net carbon emissions-ie, if the health sector were a country, it would be the fifth largest emitter on the planet. 2The authors of this article are based in the UK, but the content is relevant for all healthcare teams worldwide, providing sustainable clinical healthcare principles that can be integrated into daily practice, healthcare improvement activity, education, leadership, and research.It also introduces a series of papers, Towards net zero healthcare, written by groups in various countries and aimed more directly at specialty teams.
Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia
Authors: Qian Wang, Wen‐zhi Cai, Qin‐rong Wang, Ming‐qing Zhu, Ling‐zhi Yan, Yan Yu, Xie‐bing Bao, Hong‐jie Shen, Hong Yao, Jun‐dan Xie, Tong‐tong Zhang, Ling Zhang, Xiao‐yu Xu, Zhe Shan, Hong Liu, Jian‐nong Cen, Dan‐dan Liu, Jin‐lan Pan, Da‐ru Lu, Jia Chen, Yang Xu, Ri Zhang, Ying Wang, Sheng‐li Xue, Miao Miao, Yue Han, Xiao‐wen Tang, Hui‐ying Qiu, Ai‐ning Sun, Jin‐yan Huang, Hai‐ping Dai, De‐pei Wu, Su‐ning Chen
Journal: American Journal of Hematology (2022)

Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.
Single-Cell Analysis Reveals a CD4+ T-cell Cluster That Correlates with PD-1 Blockade Efficacy
Authors: Hiroshi Kagamu, Satoshi Yamasaki, Shigehisa Kitano, Ou Yamaguchi, Atsuto Mouri, Ayako Shiono, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Kunihiko Kobayashi, Yae Kanai, Tatsuhiro Shibata, Katsuhisa Horimoto
Journal: Cancer Research (2022)

Abstract CD4+ T-cell immunity helps clonal proliferation, migration, and cancer cell killing activity of CD8+ T cells and is essential in antitumor immune responses. To identify CD4+ T-cell clusters responsible for antitumor immunity, we simultaneously analyzed the naïve-effector state, Th polarization, and T-cell receptor clonotype based on single-cell RNA-sequencing data. Unsupervised clustering analysis uncovered the presence of a new CD4+ T-cell metacluster in the CD62Llow CD4+ T-cell subpopulation, which contained multicellular clonotypes associated with efficacy of programmed death-ligand 1 (PD-1) blockade therapy. The CD4+ T-cell metacluster consisted of CXCR3+CCR4−CCR6+ and CXCR3−CCR4−CCR6+ cells and was characterized by high expression of IL7 receptor and TCF7. The frequency of these cells in the peripheral blood significantly correlated with progression-free survival and overall survival of patients with lung cancer after PD-1 blockade therapy. In addition, the CD4+ metacluster in the peripheral blood correlated with CD4+ T-cell infiltration in the tumor microenvironment, whereas peripheral Th1 correlated with local CD8+ T-cell infiltration. Together, these findings suggest that CD62Llow CCR4−CCR6+ CD4+ T cells form a novel metacluster with predictive potential of the immune status and sensitivity to PD-1 blockade, which may pave the way for personalized antitumor immunotherapy strategies for patients. Significance: The identification of a new CD4+ T-cell metacluster that corresponds with immune status could guide effective tumor treatment by predicting response to immunotherapy using peripheral blood samples from patients.
Endometriosis-Associated Mesenchymal Stem Cells Support Ovarian Clear Cell Carcinoma through Iron Regulation
Authors: Huda I. Atiya, Leonard Frisbie, Ester Goldfeld, Taylor Orellana, Nicole Donnellan, Francesmary Modugno, Michael Calderon, Simon Watkins, Rugang Zhang, Esther Elishaev, Thing Rinda Soong, Anda Vlad, Lan Coffman
Journal: Cancer Research (2022)

Abstract Ovarian clear cell carcinoma (OCCC) is a deadly and treatment-resistant cancer, which arises within the unique microenvironment of endometriosis. In this study, we identified a subset of endometriosis-derived mesenchymal stem cells (enMSC) characterized by loss of CD10 expression that specifically support OCCC growth. RNA sequencing identified alterations in iron export in CD10-negative enMSCs and reciprocal changes in metal transport in cocultured OCCC cells. CD10-negative enMSCs exhibited elevated expression of iron export proteins hephaestin and ferroportin and donate iron to associated OCCCs, functionally increasing the levels of labile intracellular iron. Iron is necessary for OCCC growth, and CD10-negative enMSCs prevented the growth inhibitory effects of iron chelation. In addition, enMSC-mediated increases in OCCC iron resulted in a unique sensitivity to ferroptosis. In vitro and in vivo, treatment with the ferroptosis inducer erastin resulted in significant death of cancer cells grown with CD10-negative enMSCs. Collectively, this work describes a novel mechanism of stromal-mediated tumor support via iron donation. This work also defines an important role of endometriosis-associated MSCs in supporting OCCC growth and identifies a critical therapeutic vulnerability of OCCC to ferroptosis based on stromal phenotype. Significance: Endometriosis-derived mesenchymal stem cells support ovarian clear cell carcinoma via iron donation necessary for cancer growth, which also confers sensitivity to ferroptosis-inducing therapy.
Cellular immunotherapy for medulloblastoma
Authors: Michael Y Schakelaar, Matthijs Monnikhof, Sandra Crnko, Emma W Pijnappel, Jan Meeldijk, Toine ten Broeke, Niels Bovenschen
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, making up ~20% of all primary pediatric brain tumors. Current therapies consist of maximal surgical resection and aggressive radio- and chemotherapy. A third of the treated patients cannot be cured and survivors are often left with devastating long-term side effects. Novel efficient and targeted treatment is desperately needed for this patient population. Cellular immunotherapy aims to enhance and utilize immune cells to target tumors, and has been proven successful in various cancers. However, for MB, the knowledge and possibilities of cellular immunotherapy are limited. In this review, we provide a comprehensive overview of the current status of cellular immunotherapy for MB, from fundamental in vitro research to in vivo models and (ongoing) clinical trials. In addition, we compare our findings to cellular immunotherapy in glioma, an MB-like intracranial tumor. Finally, future possibilities for MB are discussed to improve efficacy and safety.
Targeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma
Authors: Irina Korovina, Anne Vehlow, Achim Temme, Nils Cordes
Journal: Neuro-Oncology (2022)

Glioblastoma (GBM) is a fast-growing primary brain tumor characterized by high invasiveness and resistance. This results in poor patient survival. Resistance is caused by many factors, including cell-extracellular matrix (ECM) interactions. Here, we addressed the role of adhesion protein integrin α2, which we identified in a high-throughput screen for novel potential targets in GBM cells treated with standard therapy consisting of temozolomide (TMZ) and radiation.In our study, we used a range of primary/stem-like and established GBM cell models in vitro and in vivo. To identify regulatory mechanisms, we employed high-throughput kinome profiling, Western blotting, immunofluorescence staining, reporter, and activity assays.Our data showed that integrin α2 is overexpressed in GBM compared to normal brain and, that its deletion causes radiochemosensitization. Similarly, invasion and adhesion were significantly reduced in TMZ-irradiated GBM cell models. Furthermore, we found that integrin α2-knockdown impairs the proliferation of GBM cells without affecting DNA damage repair. At the mechanistic level, we found that integrin α2 affects the activity of activating transcription factor 1 (ATF1) and modulates the expression of extracellular signal-regulated kinase 1 (ERK1) regulated by extracellular signals. Finally, we demonstrated that integrin α2-deficiency inhibits tumor growth and thereby prolongs the survival of mice with orthotopically growing GBM xenografts.Taken together our data suggest that integrin α2 may be a promising target to overcome GBM resistance to radio- and chemotherapy. Thus, it would be worth evaluating how efficient and safe the adjuvant use of integrin α2 inhibitors is to standard radio(chemo)therapy in GBM.
Erratum. Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes. Diabetes Care 2022;45:2189–2201
Authors: Randy L. Anderson, Linda A. DiMeglio, Adrian P. Mander, Colin M. Dayan, Peter S. Linsley, Kevan C. Herold, Marjana Marinac, Simi T. Ahmed
Journal: Diabetes Care (2022)

In the article cited above, the affiliation for author Marjana Marinac appeared incorrectly due to a journal composition error; Dr. Marinac's correct affiliation is JDRF International, New York, NY. Additional typographical errors introduced during production have also been corrected. In Table 1, the term "B cell" was used instead of "β-cell" three times. The correct table text is "β-cell-directed therapies," "β-cell survival," and "β-cell secretory capacity." In Fig. 1, upper right quadrant, the heading appeared as "Trial Risk." The correct heading is "Trial Risks." In Table 1, minor formatting and language edits have been made for clarity and consistency within columns. In Duality of Interest, the following statement was given for author Randy L. Anderson: "R.L.A. was a JDRF board director at the time of ideation of the manuscript and has since become an employee of Provention Bio, Inc." It would be more accurate to state, "R.L.A. was a JDRF board director at the time of ideation of the manuscript and is a consultant to Provention Bio, Inc." The online version of the article (https://doi.org/10.2337/dc22-0308) has been updated to reflect these changes.
Evolutionary Responses of a Reef-building Coral to Climate Change at the End of the Last Glacial Maximum
Authors: Jia Zhang, Zoe T Richards, Arne A S Adam, Cheong Xin Chan, Chuya Shinzato, James Gilmour, Luke Thomas, Jan M Strugnell, David J Miller, Ira Cooke
Journal: Molecular Biology and Evolution (2022)

Abstract Climate change threatens the survival of coral reefs on a global scale, primarily through mass bleaching and mortality as a result of marine heatwaves. While these short-term effects are clear, predicting the fate of coral reefs over the coming century is a major challenge. One way to understand the longer-term effect of rapid climate change is to examine the response of coral populations to past climate shifts. Coastal and shallow-water marine ecosystems such as coral reefs have been reshaped many times by sea-level changes during the Pleistocene, yet few studies have directly linked this with its consequences on population demographics, dispersal, and adaptation. Here we use powerful analytical techniques, afforded by haplotype-phased whole-genomes, to establish such links for the reef-building coral, Acropora digitifera. We show that three genetically distinct populations are present in northwestern Australia, and that their rapid divergence since the last glacial maximum (LGM) can be explained by a combination of founder-effects and restricted gene flow. Signatures of selective sweeps, too strong to be explained by demographic history, are present in all three populations and overlap with genes that show different patterns of functional enrichment between inshore and offshore habitats. In contrast to rapid divergence in the host, we find that photosymbiont communities are largely undifferentiated between corals from all three locations, spanning almost 1000 km, indicating that selection on host genes, and not acquisition of novel symbionts, has been the primary driver of adaptation for this species in northwestern Australia.
Sequence Divergence and Retrotransposon Insertion Underlie Interspecific Epigenetic Differences in Primates
Authors: Mayu Hirata, Tomoko Ichiyanagi, Hirokazu Katoh, Takuma Hashimoto, Hikaru Suzuki, Hirohisa Nitta, Masaki Kawase, Risako Nakai, Masanori Imamura, Kenji Ichiyanagi
Journal: Molecular Biology and Evolution (2022)

Abstract Changes in the epigenome can affect the phenotype without the presence of changes in the genomic sequence. Given the high identity of the human and chimpanzee genome sequences, a substantial portion of their phenotypic divergence likely arises from epigenomic differences between the two species. In this study, the transcriptome and epigenome were determined for induced pluripotent stem cells (iPSCs) generated from human and chimpanzee individuals. The transcriptome and epigenomes for trimethylated histone H3 at lysine-4 (H3K4me3) and at lysine-27 (H3K27me3) showed high levels of similarity between the two species. However, there were some differences in histone modifications. Although such regions, in general, did not show significant enrichment of interspecies nucleotide variations, gains in binding motifs for pluripotency-related transcription factors, especially POU5F1 and SOX2, were frequently found in species-specific H3K4me3 regions. We also revealed that species-specific insertions of retrotransposons, including the LTR5_Hs subfamily in human and a newly identified LTR5_Pt subfamily in chimpanzee, created species-specific H3K4me3 regions associated with increased expression of nearby genes. Human iPSCs have more species-specific H3K27me3 regions, resulting in more abundant bivalent domains. Only a limited number of these species-specific H3K4me3 and H3K27me3 regions overlap with species-biased enhancers in cranial neural crest cells, suggesting that differences in the epigenetic state of developmental enhancers appear late in development. Therefore, iPSCs serve as a suitable starting material for studying evolutionary changes in epigenome dynamics during development.